It is estimated that 10% of the population is affected by sensorineural or "nerve" deafness that usually arises from sensory hair cell loss or damage. Sensory deficits resulting from hair cell loss have been considered irreversible because the production of human hair cells ceases before birth. In contrast, hair cells are produced postembryonically in the ears of cold-blooded and some warm-blooded vertebrates (birds), and thousands of new hair cells can be replaced through trauma-evoked regenerative proliferation. Findings showing that supporting cells can proliferate in the balance organs of mature mammals and auditory organ of neonatal mammals under certain circumstances suggest that hair cell regeneration may be inducible in the human ear someday. In order to develop clinical therapies that will bring about hair cell regeneration in the human ear, we must identify the cellular and molecular signals responsible for triggering the regenerative proliferation of inner ear supporting cells after hair cell death, and determine how these cells go on to form hair cells. The goal of the proposed research is to identify factors that regulate regenerative replacement of hair cells in the ears of warm-blooded vertebrates during postembryonic life. This application proposes to investigate the following hypotheses: 1) Members of the TGF2 superfamily regulate progenitor cell proliferation in mature inner ear sensory receptor epithelia, and 2) Robust regenerative proliferation of progenitor cells in mature inner ear sensory epithelia may require a simultaneous release from tonic negative regulation coupled with mitogenic signaling by the TGF2 pathway. These hypotheses will be tested using a combination of techniques, including cell culture, quantitative RT-PCR, cell localization, and mouse genetics. PUBLIC HEALTH RELEVANCE: Inner ear sensory hair cell loss in humans is permanent and cumulative, whereas non-mammalian vertebrates robustly make new hair cells to replace those that have been lost after damage. We seek to identify ways to stimulate hair cell regeneration in humans by inducing cells in the mature sensory receptor epithelia to proliferate. We are investigating the role of transforming growth factor beta (TGF2) signaling in regulating the proliferation of progenitor cells in mature inner ear sensory epithelia.